title: Phase I and pharmacodynamic study of an orally administered novel inhibitor of histone deacetylases, SB939, in patients with refractory solid malignancies.
abstract: BACKGROUND
  The objective of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SB939, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies.
  
  
  METHODS
  Dose-escalating cohorts of three to six patients received SB939 orally thrice weekly for 3 weeks in a 4-week cycle. Acetylated histone H3 (acH3) was measured in peripheral blood mononuclear cells (PBMCs).
  
  
  RESULTS
  Thirty patients treated at one of five doses (10-80 mg/day) received 79 cycles of SB939 (range, 1-12 cycles). Dose-limiting toxic effects were fatigue, hypokalemia, troponin T elevation, and QTc prolongation. Peak plasma concentration (C(max)) and area under the concentration-time curve extrapolated to infinity increased dose proportionally. The MTD of SB939 was 80 mg/day. The mean elimination half-life and oral clearance of SB939 were 7.2 ± 0.6 h and 53.0 ± 8.5 l/h, respectively, with no substantial accumulation on day 15. An increase in acH3 was observed at hour 3 and correlated with dose and C(max). Stable disease was seen in several tumor types treated at ≥40 mg. HDAC inhibition was consistently observed at 60 mg, the recommended dose.
  
  
  CONCLUSIONS
  SB939 can be safely administered at the recommended dose and reaches plasma levels that strongly inhibit HDAC in PBMCs. These data support further efficacy studies of SB939.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore; Department of Haematology-Oncology, National University Hospital.
authors.forename: W P
authors.initials: WP
authors.lastname: Yong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore; Department of Haematology-Oncology, National University Hospital. Electronic address: phcgbc@nus.edu.sg.
authors.forename: B C
authors.initials: BC
authors.lastname: Goh
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore; Department of Haematology-Oncology, National University Hospital.
authors.forename: R A
authors.initials: RA
authors.lastname: Soo
authors.affiliation: Department of Medical Oncology, National Cancer Centre.
authors.forename: H C
authors.initials: HC
authors.lastname: Toh
authors.affiliation: S*BIO Pte Ltd, Singapore, Singapore.
authors.forename: K
authors.initials: K
authors.lastname: Ethirajulu
authors.affiliation: S*BIO Pte Ltd, Singapore, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Wood
authors.affiliation: S*BIO Pte Ltd, Singapore, Singapore.
authors.forename: V
authors.initials: V
authors.lastname: Novotny-Diermayr
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore; Department of Haematology-Oncology, National University Hospital.
authors.forename: S C
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore; Department of Haematology-Oncology, National University Hospital.
authors.forename: W L
authors.initials: WL
authors.lastname: Yeo
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore; Department of Haematology-Oncology, National University Hospital.
authors.forename: D
authors.initials: D
authors.lastname: Chan
authors.affiliation: Department of Medical Oncology, National Cancer Centre.
authors.forename: D
authors.initials: D
authors.lastname: Lim
authors.affiliation: Department of Haematology-Oncology, National University Hospital.
authors.forename: E
authors.initials: E
authors.lastname: Seah
authors.affiliation: Department of Haematology-Oncology, National University Hospital.
authors.forename: R
authors.initials: R
authors.lastname: Lim
authors.affiliation: S*BIO Pte Ltd, Singapore, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D056572:Histone Deacetylase Inhibitors; C557525:SB939 compound; D006655:Histone Deacetylases